Many important drugs are hydrophobic and have limited solubility in water. In order to attain the expected therapeutic effects of such drugs, it is usually required that a solubilized form of the drug be administered to a patient. For this purpose there have been developed a number of methods which are based on the use of: auxillary solvents; surfactants; soluble forms of the drug, e.g., salts and solvates; chemically modified forms of the drug, e.g., prodrugs; soluble polymer-drug complexes; special drug carriers such as liposomes; and others. Each of the above methods is hampered by one or more particular problems, e.g., the method based on the use of a surfactant to solubilize hydrophobic drugs has problems in that most surfactants are relatively toxic and precipitation of the hydrophobic drug occurs when subjected to dilution. European Patent EP 0645145 discloses a method of solubilizing a typical poorly water soluble drug, paclitaxel, by use of Cremophor EL™, a polyoxyethylene castor oil derivative. The use of these surfactants, however, is restricted due to toxic side effects such as hypersensitivity. They have limitations in that their poor ability to stabilize micelles can cause precipitation of the drug when the micellar solution is either stored or is to remain in place for an extended period of time.
In recent years, polymeric micelles have been investigated as potential carriers for poorly water soluble drugs. Efforts have been made for the preparation, characterization and pharmaceutical application of polymeric micelles. For example, see M. Jones, et al., Polymeric micelles—a new generation of colloidal drug carriers, Eur. J. Pharm. Biopharm. 48(1999) 101–111. Polymeric micelles provide attractive characteristics in two major aspects: (a) they can solubilize poorly water soluble, or hydrophobic drugs in their hydrophobic inner core; and (b) they can avoid uptake of the drug by the RES (reticuloendothelial system) or the MPS (mononuclear phagocytes system) in vivo.
Polymeric micelles are characterized by a core-shell structure in aqueous media that results from the amphiphilic block copolymers having hydrophobic (core) and hydrophilic (shell) segments. A poorly water soluble drug is entrapped within the hydrophobic core of the micelle. There has been considerable research in the development of A-B, A-H-A, or B-A-B block copolymers having a hydrophilic A block and a hydrophobic B block. As a drug carrier, it is preferred that the hydrophobic B(inner micelle core block) comprises a biodegradable polymer such as poly-DL-lactide, poly-ε-caprolactone or poly(γ-benzyl-L-aspartate) and the hydrophilic A (outer micelle shell block) be a polymer such as polyethylene glycol which is capable of interacting with plasma proteins and cell membranes.
Polymeric micelles can provide for prolonged systemic circulation time due to their small size (<100 nm), their hydrophilic shell which minimizes uptake by the MPS, and their high molecular weight which prevents renal excretion (K. Katasoka, Design of nanoscopic vehicles for drug targeting based on micellization of amphiphilic block copolymers, J. Macromol. Sci.—Pure Appl. Chem A31(1994) 1759–1769). Additionally, H. Maeda showed experimental evidence supporting the enhanced permeability and retention (EPR) effect of macromolecules in cancer chemotherapy. The tumor vessels are more leaky and less permiselective than normal vessels, and accumulation of polymeric micelles in tumors is explained by this increased vascular permeability and the lack of lymphatic drainage in tumors (H. Maeda, The tumor blood vessel as an ideal target for macromolecular anticancer agents, J. Control. Rel. 19(1992) 315–324).
Among various pharmaceutical applications of polymeric micelles, research has been focused on the parenteral administration of anticancer drugs using polymeric micelles because of the above-described advantages, such as a long circulation time in vivo, and drug targeting by the EPR effect.
Taxanes, including paclitaxel and its analogues, that exert antitumor activity due to inhibition of cell proliferation by preventing microtuble assembly, are promising anticancer agents and their preparation methods and application for chemotherapy have been widely studied. They are now available from various routes of supply such as extraction from the bark or needles of the pacific yew tree, biological method of tissue culture, or chemical synthesis. Since paclitaxel is practically insoluble in water (solubility of less than 0.01 mg/mL), several compositions to solubilize or disperse the drug in infusion fluid have been proposed for parenteral administration to patients. Bristol-Myers Squibb introduced an injectable composition containing paclitaxel, Taxol®, and this formulation is the only one which has been approved for human use by the FDA. Taxol® is a solution in which a mixture of paclitaxel and polyethoxylated castor oil (Cremophor® EL, BASF Aktiengesolischaft) is dissolved in alcohol. However, Cremophor® EL has a potential for inducing various side effects including anaphylactic reactions. Additionally, the Cremophor® EL in the Taxol® formulation causes the leaking of harmful plasticizers into the infusion fluid from the infusion bags or plastic tubes.
Intensive studies have been made in an effort to overcome the shortcomings of the Taxol® formulation, and as a result, several compositions containing paclitaxel are known as substitutes for the Taxol® formulation. U.S. Pat. No. 5,877,205 discloses a composition formulated in such a manner that pacilataxel is dissolved in an organic solvent followed by addition of secondary solvent to stabilize the drug in solution for subsequent final dilution in an aqueous lipid emulsion. U.S. Pat. No. 5,922,754 discloses another composition comprising paclitaxel, an acid, water, and mixture of some organic solvents such as triacetin, alcohol, and Solutol™ (BASF, polyethylene glycol ester of 12-hydroxystearic acid).
Although the solution of the above formulation is stable and does not precipitate for more than 72 hours (3 days) at room temperature while the solution of the Taxol® formulation is stable for 27 hours, there is an important limitation to their use in the body because the formulations still contain organic solvents, such as dimethyl acetamide, or excess amounts of Solutol™ (LD50[mouse, iv] of Polyoxyl 20 Stearate=0.87 g/kg), which is more toxic than Cremophor EL (LD50[mouse, iv]=2.5 g/kg). [LD50 from Handbook of Pharmaceutical Exipients, 2nd ed., American Pharmaceutical Association].
Therefore, while polymeric micelles seem to be one of the most advantageous carriers for the delivery of poorly water soluble drugs, such as paclitaxel or other anti-cancer agents, problems remain due to their lack of stability in infusion fluid or body fluid. X. Zhang et al, reported that a diblock copolymer of polylactide and monomethoxypolyethylene glycol(mPEG) was useful as a carrier of paclitaxel (X. Zhang et al. Development of amphiphilic diblock copolymers as micellar carriers of taxol, Int. J. Pharm. 132(1996) 195–206). The formulation dissolves paclitaxel by incorporating the drug into a polymeric micelle in aqueous media. This formulation has an advantage in that the materials employed in this formulation are non-toxic and their hydrolysis products are easily eliminated from the body, thus, overcoming prior art shortcomings in compositions containing paclitaxel, such as the Taxol® formulation, and formulations shown in U.S. Pat. Nos. 5,877,205 and 5,922,754. The formulation shown in Zhang et al., however, still has a disadvantage in that, due to unstable micellar formation, the drug is precipitated from the micelle into the aqueous infusion fluid within 48 hours.
Although polymeric micelles would seem to be ideal carriers for poorly water soluble drugs because of their distinct advantages, such as small size, high solubility, simple sterilization, controlled release of drugs, the physical stability of such carriers limits their application for pharmaceutical use.